Factors affecting the response to inhibition of drug metabolism by cimetidine‐dose response and sensitivity of elderly and induced subjects.

Feely, J.; Pereira, Leonardo Régis Leira; Guy, Elizabeth; Hockings, N.

doi:10.1111/j.1365-2125.1984.tb05002.x

Cited by 69 publications

(30 citation statements)

References 23 publications

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“…This is O consistent with studies showing that cimetidine produces 00 similar inhibition of both antipyrine (4) and theophylline (22) O in young and elderly individuals. However, it does not -O explain the previous reports (12,15,19) of exaggerated o inhibitory effects of ciprofloxacin in some elderly patients.…”

Section: Resultssupporting

confidence: 81%

“…Our data are also consistent with studies demonstrating an average decrease in theophylline clearance of 20 to 30% with ciprofloxacin (9,11,17). These reports suggest that ciprofloxacin is one of the more potent inhibitors of oxidative metabolism in clinical use today, with the magnitude of inhibition being roughly comparable to that of cimetidine (4,22).…”

Section: Resultssupporting

confidence: 80%

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Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin

Waite

Rybak

Krakovsky

et al. 1991

Antimicrob Agents Chemother

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Case reports suggest that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin may be greater in elderly subjects. We examined the effect of oral ciprofloxacin on antipyrine disposition in 13 young (ages, 23 to 34 years) and 9 elderly (ages, 65 to 82 years) healthy volunteers. Ciprofloxacin decreased antipyrine oral clearance in young and elderly subjects (P < 0.05), with the average decreases being similar in both groups (23.3% for the young subjects and 27.9% for the elderly subjects). Ciprofloxacin concentrations in serum were significantly higher (mean, 57%) in the elderly. The formation clearance of 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was also significantly decreased in both groups of subjects; however, norantipyrine formation, accounting for 15 to 20% of antipyrine clearance, was reduced only in the elderly. These results suggest that elderly subjects are not more sensitive to the inhibitory effect of ciprofloxacin on antipyrine metabolism. However, careful clinical monitoring is necessary with all patients, irrespective of age, taking ciprofloxacin concomitantly with drugs primarily eliminated by the cytochrome P-450 system.Ciprofloxacin is a fluoroquinolone antibiotic with widespread therapeutic application because of its broad spectrum of antibacterial activity, oral effectiveness, and low incidence of serious adverse effects. Studies over the past few years have established that several fluoroquinolones, including ciprofloxacin, inhibit the oxidative hepatic metabolism of a number of substrates (3). Most of these studies have involved young healthy volunteers. However, case reports and a retrospective study suggest that the magnitude of inhibition may be greater in elderly subjects. Raoof et al. (12) evaluated the effect of ciprofloxacin on theophylline concentrations in 33 hospitalized patients and found that the patients who experienced significant increases in theophylline concentrations were older than those.who did not. Case reports by Rybak et al. (15) and Thomson et al. (19) described elderly patients (82 and 92 years of age, respectively) with therapeutic (10 to 15 mg/liter) theophylline concentrations who experienced increases to more than 30 mg/liter after starting therapy with ciprofloxacin. Estimated theophylline clearance decreased by 56 and 64%, respectively, in these reports, substantially greater than the average decrease of 15 to 30%o observed in studies with young healthy volunteers (9,11,17).In addition to the possibility of an enhanced inhibitory response to ciprofloxacin in the elderly, drug interactions are more likely in this age group as a result of the large number of medications consumed. Therefore, the purpose of this study was to prospectively test the hypothesis that the magnitude of inhibition of oxidative metabolism produced by ciprofloxacin is greater in elderly than in young individuals by comparing effects on the disposition of antipyrine and its major metabolites. MATERIALS AND METHODS Subjects. Thirteen young healthy volu...

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Section: Resultssupporting

confidence: 81%

Section: Resultssupporting

confidence: 80%

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin

Waite

Rybak

Krakovsky

et al. 1991

Antimicrob Agents Chemother

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“…1.5% fall in antipyrine clearance although the drug was given 4 times daily (Feely et al, 1984). CMT's short half-life may explain the smaller effect encountered in this study with a twice daily regimen (Freston, 1982).…”

Section: Discussionmentioning

confidence: 45%

Effects of cimetidine on carbamazepine auto‐ and hetero‐induction in man.

Macphee¹,

Thompson²,

Scobie³

et al. 1984

Brit J Clinical Pharma

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1 The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme-inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. 2 CMT alone had no significant effect on antipyrine kinetics, urinary 6,-hydroxycortisol excretion or leucocyte 8-aminolaevulinic acid synthase (ALA.S) activity. 3 CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P < 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. 4 Antipyrine clearance and urinary 6 ,3-hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P < 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 P-hydroxycortisol excretion was unaffected.5 Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P < 0.05). CBZ half-life fell by 36% and clearance rose by 29% (both P < 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. 6 CMT inhibits CBZ auto-and hetero-induction in man. 7 Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.

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“…However, cimetidine mediated enzyme inhibition is relatively larger during administration of the inducer, rifampicin (Feely et al, 1984). On the other hand cimetidine decreased clearance 0.70 fold during antipyrine induction in period II, which is what would have been expected during cimetidine treatment of non-induced subjects (D0ssing et al, 1983).…”

Section: Discussionmentioning

confidence: 69%

“…In the present setting antipyrine clearance was depressed further after 3 than after 1 day of disulfiram treatment. This delayed effect is in contrast to the immediate effect cimetidine exerts on hepatic drug metabolism (D0ssing et al, 1983;Feely et al, 1984). The second and the third study period were undertaken because antipyrine is capable of stimulating microsomal drug metabolism per se in the doses used (Ohnhaus & Park, 1979), amounting to a 1.28…”

Section: Discussionmentioning

confidence: 99%

Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.

Loft¹,

Sonne²,

Pilsgaard³

et al. 1986

Brit J Clinical Pharma

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We investigated the effect of concomitantly administered disulfiram and cimetidine on antipyrine elimination. On day 1, 2, 4 and 6 of two periods of 6 days one sample antipyrine saliva clearance (APC) was measured in nine healthy volunteers. From day 2 to 6 of period I disulfiram 400 mg dayf1 was administered and on day 5 and 6 cimetidine 1000 mg day-1 was added. In period II only cimetidine was given (on days 5 and 6). On day 4 of period II APC was increased 1.3 fold, probably due to self-induction by repeated antipyrine administration. Taking this into account disulfiram and cimetidine separately decreased APC 0.64 and 0.70 times, respectively. When both inhibitors were given APC was reduced 0.52 times. The results suggest that the effects of cimetidine and disulfiram on antipyrine elimination are additive.Keywords disulfiram cimetidine antipyrine inhibition of drug metabolism

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Factors affecting the response to inhibition of drug metabolism by cimetidine‐dose response and sensitivity of elderly and induced subjects.

Cited by 69 publications

References 23 publications

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin

Influence of subject age on the inhibition of oxidative metabolism by ciprofloxacin

Effects of cimetidine on carbamazepine auto‐ and hetero‐induction in man.

Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration.

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